Aerosol therapy can be accomplished by aerosolization of a formulation (e.g., a drug formulation or diagnostic agent formulation) and inhalation of the aerosol. The formulation can be used to treat lung tissue locally and/or be absorbed into the circulatory system to deliver the drug systemically. Where the formulation contains a diagnostic agent, the formulation can be used for diagnosis of, for example, conditions and diseases associated with pulmonary dysfunction. In general, aerosolized particles for respiratory delivery must have a diameter of 12 microns or less. However, the preferred particle size varies with the site targeted (e.g, delivery targeted to the bronchi, bronchia, bronchioles, alveoli, or circulatory system). For example, topical lung treatment can be accomplished with particles having a diameter in the range of 0.01 to 12.0 microns. Effective systemic treatment requires particles having a smaller diameter, generally in the range of 0.5 to 6.0 microns, while effective ocular treatment is adequate with particles having a larger diameter, generally 15 microns or greater, generally in the range of 15-100 microns.
Generation of aerosolized particles and their respiratory delivery is generally accomplished by three distinct methodologies. One method uses a device known as a xe2x80x9cmetered dose inhalerxe2x80x9d (MDI). Drugs delivered using an MDI are dispersed in a low boiling point propellant (e.g., a chlorofluorocarbon or hydrofluorocarbon) and loaded in a pressurized canister. A metered amount of the drug/propellant formulation is released from the MDI by activating a valve on the canister. The propellant xe2x80x9cflashesxe2x80x9d or quickly evaporates and particles of the drug are inhaled by the patient. Although MDIs provide a self-contained, easily portable device, the propellants have adverse environmental effects. In addition, it is difficult to reliably deliver a precise dosage of drug using an MDI. The patient frequently actuates the device at the incorrect point during the breathing cycle, or breathes at the wrong flow rate while inhaling the drug. Thus, patients may receive inconsistent doses, sometimes inspiring too little medication, other times taking a second dose after a partial failure and thereby receiving too much medication.
Breath actuated drug delivery devices, which attempt to overcome the dosing problems of MDIs, are activated to release a dose when the patient""s inspiratory flow crosses a fixed threshold. However, the patient""s inspiratory effort may not be sufficient to satisfy the threshold to trigger drug release. Or, although the patient""s inspiration effort may be sufficient to release a metered dose, the inspired volume following the release may not be sufficient to cause the aerosol medication to pass into the desired portion of the patient""s airways. Finally, whether breath-actuated or not, MDIs generate an aerosol that can contain particles of very different sizes. Larger particles are not delivered to the same site in the lung and/or at the same rate as the smaller particles in the aerosol. The production of an aerosol of varying particle size thus makes the delivery of a precise, reproducible dosage of medication or diagnostic agent to the desired regions of the respiratory tract extremely difficult if not impossible.
The second method for generation of aerosolized particles for respiratory delivery uses devices known as xe2x80x9cdry powder inhalersxe2x80x9d (DPI). DPIs typically use bursts of air to entrain small amounts of the drug, thus forming a dust cloud of dry drug particles. DPIs do not require the propellants of MDIs. However, like MDIs, DPIs form aerosols composed of many different sizes of particles, making the delivery of a precise dose to a desired site in the respiratory tract difficult.
Nebulizers, devices used in a third method of respiratory drug delivery, utilize various means to create a fog or mist from an aqueous solution or suspension containing a pharmaceutically active drug. The mist created by the nebulizer device is directed towards the face of the patient and inhaled through the mouth and/or nose. The formulation delivered with nebulizers is sometimes diluted prior to delivery. The entire diluted formulation must generally be administered within a single dosing event in order to maintain the desired level of sterility.
Nebulizer devices can be quite useful when the precise dosing of the drug being delivered to the patient is not of particular importance, e.g., for treatment of a patient with a bronchodilator until he feels some improvement in lung function. When precise dosing is more important, the nebulizer device and delivery methodology suffers from many of the disadvantages of metered dose inhaler devices and methodology as described above. In addition, nebulizers generally are large and not easily transportable devices. Accordingly, a nebulizer can only be used within a fixed location such as the patient""s home, the doctor""s office and/or hospital. Yet another disadvantage of nebulizers is that they produce an aerosol which has a distribution of particle sizes, not all of which are of appropriate size to reach the targeted areas of the lung.
An aerosolization device can also be used to deliver treatment to the eye. Ophthalmic treatment fluids are commonly administered to the eye by means of eye drops or ointments. The use of eye drops has a number of disadvantages, primarily as a consequence of the difficulty with which drops are accepted by the patient. The drops are relatively large, and the instinctive blink that is provoked by the arrival of a drop on the eye severely limits the amount or proportion of fluid that actually contacts the target area of the eye. Typically less than 10% of a 50 xcexcl drop reaches the desired site of administration, the remainder being lost by drainage, either externally or through nasolacrimal drainage. Such use of expensive treatment fluids leads to substantial uncertainty regarding the effectiveness of treatment. Ointments are associated with similar problems in their use to accomplish ocular therapy.
Various techniques for delivering treatment fluid to the eye are known. Most employ treatment systems in which treatment fluid is drawn from a reservoir and discharged in a controlled manner to the eye (see, e.g., WO96/06581). U.S. Pat. No. 3,934,585 disclosed a variety of mechanisms for delivering unit doses of treatment fluid to the human eye. For example, treatment fluid can be delivered by applying compressed air to one end of a tube resulting in the discharge of treatment fluid from the other end.
Devices and methods for controlling aerosol particle size are known in the art. For example, U.S. Pat. No. 4,926,852 described control of particle size by metering a dose of medication into a flow-through chamber that has orifices to limit the flow rate. U.S. Pat. No. 4,677,975 described a nebulizer device having baffles to remove particles above a selected size from an aerosol. U.S. Pat. No. 3,658,059 employed a baffle that changes the size of an aperture in the passage of the suspension being inhaled to select the quantity and size of suspended particles delivered. U.S. Pat. No. 5,497,944 described a method and device for generating an aerosol by passing the formulation through a small nozzle aperture at high pressure. However, devices that process the aerosol particle size after generation (e.g., by filtering the aerosol after it is formed from the formulation) are typically inefficient, wasteful, and/or require a substantially greater amount of force to generate the aerosol.
Co-owned U.S. Pat. No. 5,544,646 and U.S. patent applications Ser. Nos. 08/454,421, 08/630,391, 08/693,593 and 08/804,041 describe devices and methods useful in the generation of aerosols suitable for drug delivery. A drug formulation is forcibly applied to one side of the pore-containing membrane so as to produce an aerosol on the exit side of the membrane. Aerosols containing particles with a more uniform size distribution can be generated using such devices and methods, and can be delivered to particular locations within the respiratory tract.
One impediment to aerosol formation using prior membranes is the accumulation of a liquid layer on the exit side of the membrane. This can occur when forcible application of the formulation to the entrance side of the nozzle, rather than causing aerosolization, causes lateral spreading of liquid from the exit side, for example from poorly formed or irregular pores, or where the pressure is insufficient to consistently generate an aerosol. This liquid layer can spread to properly functioning pores and thereby disrupt their function, further degrading performance of the nozzle. This problem is particularly acute, for example, where the pores are closely or irregularly spaced, or where extrusion takes place over a significant period of time, or when the nozzle is to be used for repeated administration.
We have now invented an extrusion nozzle that is particularly well suited to extrusion of a formulation into the entraining airstream and delivery of particles having an improved size distribution to the respiratory tract. The nozzles of the invention maximize the conversion of pressure on the formulation container to kinetic energy of the formulation being extruded, and provide aerosol particles of the desired sizes.
One aspect of the invention is a nozzle for aerosolizing a formulation, said nozzle comprising a membrane having about 200 to about 1,000 holes, said holes having an average relaxed exit aperture diameter of from about 0.5 to about 1.5 xcexcm and spaced from about 30 to about 70 xcexcm apart from each other. The membrane is preferably flexible.
In a further aspect of the invention, a nozzle is provided wherein the area surrounding the exit aperture of the pores is elevated above the (otherwise substantially planar) exit side of the film so as to prevent intrusion of liquid into the exit aperture of the pores.
In another aspect of the invention, a nozzle is provided wherein the exit aperture of the pores has a smaller diameter than the entrance aperture.
In yet another aspect of the invention, a nozzle is provided wherein the pores are incompletely formed so that, upon administration of pressure to the entrance side of the film, the exit aperture is formed by bursting outward the exit side of the pores, thereby forming an elevated area preventing liquid intrusion into the exit aperture.
In a further aspect of the invention, a strip containing multiple nozzles is provided.
Another aspect of the invention is a method for aerosolizing a formulation in a way that maximizes the amount of formulation available for inhalation, comprising extruding the formulation into an airstream through a flexible, porous membrane, where the pores are from about 0.5 to about 1.5 microns in exit aperture diameter when unflexed, and are spaced about 30-70 xcexcm apart.
Still another aspect of the invention is a method for aerosolizing a formulation through a nozzle comprising such pores where the area surrounding the exit aperture of the pores is elevated above the substantially planar exit side of the membrane.
Yet another aspect of the invention is a method for aerosolizing a formulation through pores having entrance apertures wider than their exit apertures.